Project Summary A significant obstacle to the creation of the next generation of small molecule therapeutics is the lack of general and efficient methods for accessing certain stereochemically dense structures that contain functionality important for bioactivity. This MIRA application seeks to merge two productive NIGMS-funded projects broadly concerned with the laboratory preparation of chiral, functionalized bioactive small molecule building blocks. The general goal of this program is to develop new synthetic chemistry platforms that will enable the rapid and selective construction of new structures of immediate relevance for biomedical applications. We will use the structures of architecturally and functionally complex bioactive natural products as an inspiration for the invention of new synthetic methods whose utility we expect to transcend the direct application to the target of interest. Overlaid with this approach will be a focus on a subset of reactions that catalytically convert racemic mixtures to enantiopure products (dynamic kinetic resolution, DKR). Thus, a symbiotic loop between natural product chemistry and new reaction development is a projected outcome. Jervine and deoxojervine are inhibitors of the hedgehog signaling pathway and semisynthetic variants are under evaluation in oncology clinical trials. We will use the structure of the steroidal jerveratrum alkaloids as an inspiration to develop new enantioconvergent reactions that rapidly assemble the challenging fused heterocyclic portion of the molecule. The key to implementation of our strategy is the recognition that current DKR methodology is limited to a relatively small number of racemization mechanisms. A significant part of the MIRA grant is designed to dramatically expand the DKR paradigm into families of reactions that have never before been considered as candidates for enantioconvergence, particularly in the context of reactions that can rapidly assemble molecular complexity. Our approach to the neurotoxin tetrodotoxin hinges on the development of a new twofold oxidation/cycloaddition cascade sequence that quickly assembles the skeletal, functional, and stereochemical complexity that will be required for an efficient synthesis. Again, while this reaction will enable facile construction of the target structure and congeners, the greater value is projected to lie in the new chemical space that opens as a consequence of having access to a new family of rigid templates with a high level of independently addressable functionality. Finally, we will seek to develop new reaction chemistry involving ?- and ?-dicarbonyl structures. The special features of compounds containing such functional groups engender unique and enabling chemistry that we have successfully and extensively exploited. Many new manifolds will be explored under the aegis of the MIRA grant. Collectively, we expect that the MIRA research activities will advance the field of organic chemistry and be of use in biomedical endeavors by providing facile access to structures that were heretofore unknown or accessible only by virtue of methods that were inefficient and/or impractical.